The proposed research (continuation of GM65958-01) seeks (i) to continue development of the diamond microelectrode for in vitro chronoamperometric measurements of neurotransmitter release and for use in microcapillary separation techniques coupled with electrochemical detection for the analysis of catecholamine neurotransmitters and metabolites in biological fluids, and (ii) to apply these tools to the study of sympathetic neural control mechanisms of arteries and veins in hypertension. Hypertension is a major health problem in the U.S. Those suffering from chronic high blood pressure are at high risk for organ damage and cardiovascular disease. Although the risk factors are known and treatments have been developed to alleviate symptoms, little is known about the underlying biological pathways and mechanisms. A goal of our research program is to gain a better understanding of how the sympathetic nervous system influences the development and maintenance of hypertension, and what effect chronic hypertension has on the cardiovascular system function and resistance to disease. Specific aims for the research include the following. Specific Aim 1: There are differences between sympathetic neural control of arteries and veins. These differences include the neurotransmitters released, receptors and mechanisms controlling release, and termination of the actions of the neurotransmitters. We seek to understand how these processes are altered in hypertension. Specific Aim 2: Endothelin-1 (ET-1) activity is increased in DOCA-salt hypertensive rats. It is also known that sympathetic activity is elevated in these animals and that ET-1 may be involved in changing sympathetic function in hypertension. We seek to understand the mechanism of ET-1 activity and how it can modulate NE release from sympathetic nerves. We also seek to understand if ET-1 can modulate ATP release from sympathetic nerves supplying mesenteric arteries and if this response is altered in hypertension.